Background: We recently demonstrated that elexacaftor/tezacaftor/ivacaftor (ETI) improves the lung clearance index (LCI) and abnormalities in lung morphology detected by magnetic resonance imaging (MRI) in adolescent and adult patients with cystic fibrosis (CF). However, real-world data on the effect of ETI on these sensitive outcomes of lung structure and function in school-age children with CF have not been reported. The aim of this study was therefore to examine the effect of ETI on the LCI and the lung MRI score in children aged 6–11 years with CF and one or twoF508delalleles.Methods: This prospective, observational, multicentre, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and 3 months after initiation of ETI.Results: A total of 107 children with CF including 40 heterozygous forF508deland a minimal function mutation (F/MF) and 67 homozygous forF508del(F/F) were enrolled in this study. Treatment with ETI improved the median (interquartile range (IQR)) LCI in F/MF (−1.0 (−2.0– −0.1); p<0.01) and F/F children (−0.8 (−1.9– −0.2); p<0.001) from 3 months onwards. Further, ETI improved the median (IQR) MRI global score in F/MF (−4.0 (−9.0–0.0); p<0.01) and F/F children (−3.5 (−7.3– −0.8); p<0.001).Conclusions: ETI improves early abnormalities in lung ventilation and morphology in school-age children with CF and at least oneF508delallele in a real-world setting. Our results support early initiation of ETI to reduce or even prevent lung disease progression in school-age children with CF.

Background: The triple cystic fibrosis transmembrane conductance regulator modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) rapidly improves airway and systemic inflammation in people with cystic fibrosis. However, longitudinal effects on systemic inflammation and their relationship to lung function remain unknown. Methods: In this prospective, observational, multicentre study, we analysed peripheral blood neutrophil counts, C-reactive protein (CRP) and six pro-inflammatory serum cytokines in a cohort of 198 people with cystic fibrosis aged ≥6 years at baseline and follow-up visits 3, 12 and 24 months after initiation of ETI, compared to 74 age-matched healthy control participants. Results: Neutrophil counts and CRP, granulocyte colony-stimulating factor, interleukin (IL)-1β, IL-6 and IL-8 were reduced to 71%, 40%, 41%, 63%, 46% and 81% of median baseline values, respectively, after 3 months of therapy (all p<0.05), whereas monocyte chemotactic protein-1 reached 82% of baseline levels at 12 months only (p<0.05). Change from baseline to 3 months correlated with improvements in percent predicted forced expiratory volume for all systemic inflammation parameters except IL-8 (Spearman's r −0.17 to −0.42, p<0.05). All cytokines reached healthy control levels at or before 24 months. Decreased inflammation levels were sustained until 24 months for all parameters (p<0.05) except IL-6. Conclusions: Our results demonstrate that ETI exerts rapid and sustained effects on systemic inflammation associated with lung function improvements in children, adolescents and adults with cystic fibrosis in a real-world, post-approval setting. However, our data also show that individual markers of systemic inflammation remain at levels above those of healthy controls, particularly in certain subgroups, suggesting persistence or resurgence of residual systemic inflammation.

Introduction: Fibroblast growth factor 10 (FGF10) is a signaling molecule with a well‐established role for lung branching morphogenesis. Rare heterozygous, deleterious variants in the FGF10 gene are known causes of the lacrimo‐auriculo‐dento‐digital (LADD) syndrome and aplasia of lacrimal and salivary glands. Previous studies indicate that pathogenic variants in FGF10 can cause childhood Interstitial Lung Disease (chILD) due to severe diffuse developmental disorders of the lung, but detailed reports on clinical presentation and follow‐up of affected children are lacking.Methods: We describe four children with postnatal onset of chILD and heterozygous variants in FGF10, each detected by exome or whole genome sequencing.Results: All children presented with postnatal respiratory failure. Two children died within the first 2 days of life, one patient died at age of 12 years due to right heart failure related to severe pulmonary hypertension (PH) and one patient is alive at age of 6 years, but still symptomatic. Histopathological analysis of lung biopsies from the two children with early postpartum demise revealed diffuse developmental disorder representing acinar dysplasia and interstitial fibrosis. Sequential biopsies of the child with survival until the age of 12 years revealed alveolar simplification and progressive interstitial fibrosis.Discussion: Our report extends the phenotype of FGF10‐related disorders to early onset chILD with progressive interstitial lung fibrosis and PH. Therefore, FGF10‐related disorder should be considered even without previously described syndromic stigmata in children with postnatal respiratory distress, not only when leading to death in the neonatal period but also in case of persistent respiratory complaints and PH.

Background: Paediatric community-acquired pneumonia (CAP) is a leading cause of paediatric morbidity. However, particularly for outpatients with paediatric CAP, data on aetiology and management are scarce.Methods: The prospective pedCAPNETZ study multicentrically enrols children and adolescents with outpatient-treated or hospitalised paediatric CAP in Germany. Blood and respiratory specimens were collected systematically, and comprehensive analyses of pathogen spectra were conducted. Follow-up evaluations were performed until day 90 after enrolment.Results: Between December 2014 and August 2020, we enrolled 486 children with paediatric CAP at eight study sites, 437 (89.9%) of whom had radiographic evidence of paediatric CAP. Median (interquartile range) age was 4.5 (1.6–6.6) years, and 345 (78.9%) children were hospitalised. The most prevalent symptoms at enrolment were cough (91.8%), fever (89.2%) and tachypnoea (62.0%). Outpatients were significantly older, displayed significantly lower C-reactive protein levels and were significantly more likely to be symptom-free at follow-up days 14 and 90. Pathogens were detected in 90.3% of all patients (one or more viral pathogens in 68.1%; one or more bacterial strains in 18.7%; combined bacterial/viral pathogens in 4.1%). Parainfluenza virus andMycoplasma pneumoniaewere significantly more frequent in outpatients. The proportion of patients with antibiotic therapy was comparably high in both groups (92.4% of outpatientsversus86.2% of hospitalised patients).Conclusion: We present first data on paediatric CAP with comprehensive analyses in outpatients and hospitalised cases and demonstrate high detection rates of viral pathogens in both groups. Particularly in young paediatric CAP patients with outpatient care, antibiotic therapy needs to be critically debated.

Pulmonary Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease which can occur sporadically (S-LAM) or in association with tuberous sclerosis (TSC-LAM). It Is estimated that 3.4–7.8 per million women are affected worldwide (O’Mahony et al., Breathe (Sheff). 2020;16(2):2007–2020). LAM typically presents with diffusely distributed cysts of 2mm-2cm diameter in the lung parenchyma caused by infiltration and proliferation of abnormal smooth muscle-like LAM cells (McCarthy et al., Lancet Respir Med. 2021;9(11):1313–1327). 70% of cases initially present with secondary pneumothorax. Further symptoms and clinical course vary broadly, ranging from asymptomatic patients to end stage lung disease necessitating lung transplantation (O’Mahony et al., Breathe (Sheff). 2020; 16(2): 2007–2020). TSC-LAM, found almost exclusively in women of reproductive age, is caused by pathogenic variants in TSC1 or TSC2. Reports of TSC-LAM in men are controversial, due to absence of typical histopathology and/or pathogenic TSC variant. (McCarthy et al., Lancet Respir Med. 2021; 9(11): 1313–1327). To our knowledge, genetically confirmed TSC-LAM has never been described in the male pediatric population. Herein we report the first case of LAM in a male adolescent with confirmed pathogenic TSC1 variant. Article published online: 19 January 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany